16beta-halomethyl-16alpha, 17alpha-oxido steroids of the pregnane series



United States Patent 3,174,967 16fl-HALOMETHYL-16oc,l7oc-OXIDO STEROIDSOF THE PREGNANE SERIES Karl-Heinz Bork and Heinz Jurgen Mannhardt,Darmstadt, Germany, assignors to E. Merck Akfiengesellschaft, Darmstadt,Germany No Drawing. Filed Mar. 16, 1962, Ser. No. 180,358 Claimspriority, application Germany, Mar. 17, 1961,

13 Claims. crf zen-239.55

The present invention relates to new and useful 16a,l7a-oxido steroidsof the pregnane series. These new compounds are important intermediatesfor the preparation of the physiologically active l6-halomethylene andI'S-dehydro-l6-halomethyl steroids of the corticoid series.

The main object of this invention, therefore is to provide novel anduseful 16a,17a-oxido steroids.

Another object is to provide a process for the manu fiacture of thenovel steroids.

Still another object is to provide a process for converting the novelcompounds of this invention into physiological active steroids.

Other objects and advantages of the invention will become apparent uponfurther study of the specification and appended claims.

The new compounds of this invention may be represented by the followingformula onnn o o l --o R.- onzx g\ in E Rs wherein R is hydrogen, a freeor esterified hydroxy group; R is hydrogen or fluorine;

R is hydrogen, methyl or fluorine;

R is H,H; H,OH, or keto; and

X is chlorine or bromine and wherein additional double bonds areoptionally present in the l-, or 6-, or land 6-positions. The newcompounds may be prepared from 16-methylene-l7a-hydroxy steroids of theFormula II.

wherein R R R and R have the above meaning and wherein further doublebonds may be present in the 1-, 6-, or 1- and 6-positions, by treatmentwith N-bromoor N-chloro-succinimide or with bromine or chlorine.

The starting materials of Formula II as defined, to be ICC used in theprocess of the present invention are well known from the pertinentliterature, for example from Tetrahedron Letters, No. 16 (1960), pp.21-32; Journal of the Chemical Society (London), 1961, p. 2821, and fromthe published German patent application 1,113,453.

The reaction of a compound of Formula II with N- bromoandN-chlorosuccinimide, respectively, is preferably effected in a watermiscible solvent such as dioxane, tetrahydrofuran, glacial acetic acidor a tertiary alcohol, especially tertiary butanol. Normally thereaction is carried out at room temperature although temperatures from20 C. up to the boiling point of the solvent are possible. The reactiontimes, in general, vary from half an hour to one day in order to producean economically satisfactory yield.

The reaction with bromine or chlorine is preferably also effected ininert solvents such as ether, chloroform, methylene chloride or glacialacetic acid. Generally, temperatures from -6 C. to room temperature(about 25 C.) are preferred, especially temperatures from 0 C. to 25 C.Depending on the starting materials, the reaction times vary from halfan hour to 3 hours to obtain economically satisfactory yields.

When R represents an esterified hyroxyl group, the hydroXy is preferablyesterified with an aliphatic monocarboxylic acid having 1-4 carbonatoms. In general, though the acyl group may be as well the radical ofhigher mono carboxylic or even dicarboxylic acids, the lower monocarboxylic acid radicals are preferred.

The new compounds of Formula I are useful intermediates for thepreparation of a large number of steroids possessing beneficialphysiological activities. Thus, they are important for the preparationof the physiologically active steroids of the formula as well as of thecorresponding A A and A -derivatives thereof. In these formulas, R to Rhave the previously indicated meanings and Y indicates fluorine,chlorine or bromine.

These steroids exhibit an outstanding antiphlogistic activity. They maybe prepared from the new steroids of Formula I by treatment with acids.Depending on the selection of the acid, 16-l1alomethyleneorl5-dehydrol6-halomethyl steroids are formed thereby. Thus, for exampleby treatment with hydrobromic acid in the presence of an inert organicsolvent, such as ether, dioxane, glacial acetic acid or acetone, thecorresponding 16-halomethylene compounds are formed whereas a treatmentwith a strong acid such as hydrochloric or hydrobromic acid in thepresence of water and a solvent miscible with water yields15-dehydro-l6-halomethyl compounds.

The 16,8-bromomethyl-16a,17a-oxido steroids according to this inventionare highly important as intermediates for the preparation of the16-fiuoromethylene and 15-dehydro-16-fluoro-methyl-corticoids.

The new compounds of the present invention wherein R represents hydrogenmay be converted into the corresponding corticoids (R :OH or O-acyl) bywell known methods, for instance, by subsequent treatment with analkaline solution of iodine and potassium acetate.

For purposes of illustration, the following examples disclose preferredembodiments of how to make the useful intermediates of the presentinvention. These embodiments, however, are not intended to be limitativeof the specification and appended claims.

Example 1 A solution of 686 mg. of chlorine in 45 ml. of chloroform isadded at -20 C. to a solution of 3 g. of 16-methylene-17a-hydroxy-progesterone in 115 ml. of anhydrous chloroformwithin 45 minutes. After standing 1 hour at room temperature, thereaction mixture is evaporated to dryness. The obtained colorless resinis dissolved in benzene and chromatographed through florisil (amagnesium-aluminum silicate). The165-chloromethyl-l6a,17a-oxido-progesterone is stripped with achloroform el-uant, and recrystallized from methanol. M.P. 155-156"; (u)+130 (chloroform); x 240 m 17,500.

Example 2 A solution of 52 mg. of bromine in 10 ml. of anhydrouschloroform is added at -20 C. to a solution of 1 g. of16-methy1ene-17a-hydroxy-progesterone in 10 ml. of an hydrouschloroform. After standing for 1 hour at room temperature, the solutionis evaporated under reduced pressure. The residual oil ischromatographed through florisil. Thel6fl-bromomethyl-l6a,l7a-oxido-progester one crystallizes from thechloroform eluates. M.P. 131- 133 C.; +106 (chloroform); x 239.5 me=l7,600.

Example 3 6.45 g. of N-chloro succinimide and 3 ml. of perchloric acid(70%) are added to a solution of 10 g. of 16-rnethylene-lh-hydroxyprogesterone in 400 ml. of dioxane and 50 ml. of Water. After standingovernight at room temperature, the reaction mixture is diluted withwater and extracted with chloroform. The chloroform extract isevaporated and the obtained 16B-ch1oromethyl-l6a,17aoxido progesteroneis recrystallized from acetone. M.P. 155156 C.

Example 4 7.6 g. of N-bromo succinimide and 3.6 ml. of perchloric acid(70%) are added to a solution of 10 g. of 16-methy1ene-l7a-hydroxyprogesterone in 40 0 ml. of dioxane. After standing for 1 hour at roomtemperature, the reaction mixture is diluted with water and extractedseveral times with chloroform. The combined extracts are washed with anaqueous solution of sodium bicarbonate and with water to neutrality andare evaporated under reduced pressure. From the residue, thel6fi-bromomethyl-16a,17a-oxido progesterone is recrystallized fromether. M.P. 131-133 C.; (a) +106 (chloroform); )t 239.5 mg, E:17,600.

Example 5 3.61 g. of N-chloro succinimide and 1.9 ml. of perchloric acid(70%) are added to a solution of 5.27 g. of6a-methyl-16-methylene-17a-hydroxy-progesterone in 230 ml. of dioxaneand 28 ml. of water. After 12 hours, 3 liters of water are added, andthe reaction mixture is ylene-17a-hydroxy-progesterone.

l extracted with methylene chloride. The combined extracts are washed toneutrality, dried and evaporated. The residue of6a-methyl-l6,8-chloromethyl-16a,17a-oxido-progesterone crystallizes uponaddition of methanol. x 239.5 mg.

Example 6 According to the method described in Example 4, the6a-methyl-l6fi-bromomethyl-l6a,17a-oxido progesterone is obtained from6a-methyl-16-methylene-17a-hydroxyprogesterone. x 240 mp.

Example 7 In accordance with the method described in Example 3, the6a-fiuoro-16B-chloromethyl-16a,17a-oxido-progesterone is prepared from6a-fluoro-16-methylene-17a-hydroxy-progesterone. A 235.5 mg.

Example 8 In accordance with the method described in Example 4, theGot-fluoro-16fi-bromomethyl-16a,l7a-oxido-progesterone is obtained from6a-fluoro-16-methylene-17a-hydroxyprogesterone. A 236 III/1..

Example 9 According to the method described in Example 5, the6-dehydro-16fi-chloromethyl-16a,17x-oxido progesterone is obtained from5.1 g. of 6-dehydro-16-methylene-17a-.

hydroxy-progesterone by the addition of only 1.46 g. ofN-chlorosuccinimide. x 282 m Example 10 1.15 g. of N-bromo succinimideand 0.45 ml. of perchloric acid (70%) are added to a solution of 2 g. of6-dehydro-16-methylene-17u-hydroxy-progesterone in ml. of dioxane and 10m1. of water. After standing for 1 hour at room temperature, thereaction mixture is worked up in the usual way. The6-dehydro-16fi-bromomethyl-161x,17a-oxido-progesterone is recrystallizedfrom acetone. x 282 m Example 11 In accordance with the method describedin Example 9, the1,6-bis-dehydro-16f3-chloromethyl-16a,17u-oxidoprogesterone is obtainedfrom 1,6-bis-dehydro-16-meth- Example 12 In accordance with the methoddescribed in Example 10, the1,6-bis-dehydro-16fl-bromomethyl-16a,l7a-oxidoprogesterone is obtainedfrom 1,6-bis-dehydro-l6-methylene-17a-hydroxy-progesterone. A 222, 256,298 m l.

Example 13 According to the method described in Example 3, the 16pchloromethyl-16a,17a-oxido-4-pregnene-21-ol-3,20- dione-21-acetate isobtained from 16-methylene-4-pregnenel7a,21-diol-3,20-dione-21-acetate.M.P. 164 C.; (oc) +125 (chloroform); )t 239.5 mg;

Example 14 According to the method described in Example 4, thebromomethyl 16a,l7a-oxido-4-pregnene-21-ol-3, 20-dione-21-acetate isobtained from. 16-methylene-4-pregnene-l7a,2l-diol-3,20-dione-2l-acetate. M.P. 130

132 C.; (00 +95 (chloroform).

Example According to the method described in Example 5, the 60:methyl-16 3-chloromethyl-16a,17a-oxido-4-pregnene-21-ol-3,20-dione-2l-acetate is prepared from 6a-methyl- 16methylene-4-pregnene-17a,21-diol-3,20-dione-2l-acetate. k 240 mp.

Example 16 According to the method described in Example 4, the 60:methyl-16,3-bromomethyl-16u,17a-oxid0-4-pregnene-2l-ol-3,20-dione-21=acetate is prepared from 6a-methyl- 16methylene-4-pregnene-17a-21-diol-3,20-dione-21-acetate. h 240.5 mu.

Example 17 According to the method described in Example 3, the 60:fluoro-16,8-chlorornethyl-l6a,17a-oxid0-4-pregnene-21-01-3,20-dione-21-acetate is obtained from 6a-fil1010- 16methylene-4-pregnene-17a,2l-diol-3,20-dione-2l-acetate. A 235.5 ma.

Example 18 In accordance with Example 4, the 6oc-fll101'0-16fi-b10-momethyl l6oc,l7oc oxido-4-pregnene-21-ol-3,ZO-dione- 2l-acetate isobtained from 6a-fiuor0-16-methylene-4-pregnene-17a,21-diol-3,2()-dione-2l-acetate. A 236 mp.

Example 19 Analogous to the method described in Example 10, the 16 8bromomethyl-l6a,17a-oxido-4,6-pregnadiene-21-01- 3,20-dione-21-acetateis obtained from 16-methylene-4,6- pregnadiene 17a21-diol-3,20-dione-2l-acetate. 282 ma.

Example 20 2.1 g. of 6a-fluoro-l6-rnethylene-1,4-pregnadiene-17a,21-diol-3,ZO-dione-Zl-acetate are dissolved in 150 m1. of Water. 0.98 g.of N-bromo succinimide and 0.46 ml. of perchloric acid (70%) are addedto this solution. After one hour, the reaction mixture is diluted withwater. The thus formed suspension is extracted with chloroform. Thecombined extracts are washed to neutrality, dried and evaporated. Fromthe oily residue the 6a-fluoro-l6flbromomethyl 16a,17x-oxido-1,4-pregnadiene-2l-ol-3,20- dione-21-acetate is obtained. M.P.154-155, (a) +26 (chloroform), )t 241.5 ma,

lfin. 351 Example 21 According to the method described in Example 10,the 1613 brornomethyl 16a,17a-oxido-4-pregnene-1113,21-diol-3,20-dione-21-acetate is prepared from16-methylene-hydrocortisone-2 l-acetate. A 240.5 m

Example 22 According to Example 10, the 6a-methyl-16B-bromomethyl160z,17oc oxido 4-pregnene-1l/3,21-diol-3,20- dione-21-acetate isobtained from 6a-methyl-l6-methylene-hydrocortisone-Zl-acetate. )t 241III/1..

Example 23 In accordance with the method given in Example 10, the16B-bromomethyl-16a,17a-oxido-1,4-pregnadiene-11B,21-diol-3,20dione-2lacetate is prepared from16-methylene-prednisolone-2l-acctate. A 241 mp.

Example 24 According to the method of Example 10, the 16,8-bromomethyl16a,l7a oxido-l,4-pregnadiene21-ol-3,l1, 20-trione-21-acetate isobtained from 2 g. of 16-methylene-prednisone-2l-acetate. x 239.5 ma.

Example 25 In accordance with the method of Example 4, the 1613-bromomethyl 16a,17aoxido-1,4-pregnadiene-115,2ldiol-3,20-dione-21-butyrate is prepared from5.36 g. of

16-methylene-prednisolone-2l-butyrate. A 241 mp.

6 Example 26 According to the method described in Example 10, the 9:1fiuoro-168-brom0me-thyl-16a,17a-oxido-1,4-pregnadiene-l15,21-diol-3,20-dione-2l-acetateis prepared from fiuoro-l6-methylene-prednisolone-2l-acetate. A 239Example 27 In accordance with the method of Example -10, the 16/8bromomethyl 1601,1711 oxido-1,4,6-pregnatriene-1lfi,2l-diol-3,20-dione-2l-acetate is prepared from 4.0 g. of16-methylene-1,4,6-pregnatriene-1 113,17a,21-ifl01-3,20-dione-21-acetate. )t 221, 256, 298 mp.

Example 28 In a manner similar to Example 4, 10 g. of16-methylene-4-pregnene-17a,21-diol-3,20-dione are reacted with 5,2 g.of N-bromo succinimide. The v16/3-bromomethyl-16a,17a-oxido-4-pregnene-21-ol-3,20-dione is recrystallized fromacetone. M.P. 254.

Example 29 According to the method described in Example 3, the 604fluoro chloromethyl 16a,17a oxido 1,4-pregnadiene-21-ol-3,20-dione-2l-acetate is obtained from 60c fluoro 16methylene 1,4 pregnadiene 17oc,21- diol-3,20-dione-2l-acetate. M.P.113118, (a) 56 (chloroform), )t 241.5 m

El a... 383

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions. Consequently, such changes and modifications are properlyequitably and intended to be within the full range of equivalence of thefollowing claims.

What is claimed is: 1. A compound selected from the group consisting ofa compound of the formula and the A A and A derivatives thereof whereinR is a member of the group consisting of hydrogen,

a free hydroxyl group and a hydroxyl group esterified with a carboxylicacid of 14 carbon atoms; R is a member of the group consisting ofhydrogen,

methyl and fluorine; X is a member of the group consisting of chlorineand bromine. 2. 16,8 chloromethyl 16a,17a oxido 4 pregnene- 3,20-dione.

3. 165 bromomethyl 16a,17a oxido 4 pregnene- 3,20-dione.

4. 16,8 chloromethyl 16a,17 x-oxido 4 pregnene-2l-ol-3,20-dione-21-acetate.

5. 16,8 bromomethyl 16cc,l7oz oxido 4 pregnene-21-ol-3,20-dione-2l-acetate.

6. 60a methyl 16 8 chloromethyl 16a,l7a-OXidO 4-pregnene-3,20-dione.

7. 6a methyl 16B bromomethyl 16a,17a oxido- 4-pregnene-3,20-dione.

8. 6a methyl 16/3 chloromethyl 16a,17a oxido-4-pregnene-21-ol-3,20-dione-2l-acetate.

7 9. 60 methyl 16/3 bromomethyl 1600,1700 oxido- References Cited by theExaminer 4-pregnene-2'l-ol-3,20-dione-2l-acetate. UNITED STATES PATENTS10. 60c fluoro 16B chloromethyl 16a,17cc oxido- 4 pregnene v21 O1 3,20dione 2Lacetate' 3,065,239 11/62 Wendler et a1. 260-39745 11. 60c fiuoro16B bromomethyl 16u,17a oxido- 5 OTHER REFERENCES "P 'l Bruckner et a1.:Chem. Berichte, v01. 94, No. 11,

1 6a fl chloromethyl 1611,17 0X1d0- November 1961, pp. 2897-2909 (page2899 primarily de- 4-pregnene-3,20-d1one. pended upon).

13. 6a fluoro 165 bromomethyl 160;,170; oxido- 4-pregnene-3,20-dione. 10LEWIS GOTTS, Primary Examiner.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THEFORMULA